The present invention concerns new and useful compounds related to the prostaglandins. More particularly, the invention pertains to novel 1,4-diaminobutane prostaglandin compounds and to novel 1-amino-4-guanidobutane prostaglandin compounds that possess enhanced biological stability, and the property to perform as a pharmaceutical storage depot for eventual in vivo circulation of the 1,4-diaminobutane prostaglandins or 1-amino-4-guanidobutane prostaglandins to prostaglandin receptive sites whereupon the subsequent metabolic separation of the prostaglandin from the 1,4-diaminobutane or 1-amino-4-guanidobutane prostaglandin compound the valuable pharmacological properties of the parent prostaglandin are made available for performing its respective physiological function. The new 1,4-diaminobutane prostaglandins and 1-amino-4-guanidobutane prostaglandins of this invention have the structure as illustrated by Formulae I: ##STR4## wherein R.sub.2 and R.sub.6 are hydrogen when Z.sub.2 is a single covalent bond and R.sub.2 and R.sub.6 are absent when Z.sub.2 is a double covalent bond; R.sub.3 is a member selected from the group consisting of keto, ##STR5## R.sub.4 is selected from the group consisting of hydrogen and ##STR6## R.sub.5 is selected from the group consisting of hydrogen, ##STR7## R.sub.6 is hydrogen when Z.sub.2 is a single bond and it is absent when Z.sub.2 is a double bond; R.sub.7 is selected from the group consisting of OH and OR.sub.9 ; R.sub.8 is selected from the group consisting of hydrogen and hydroxyl; R.sub.9 is selected from the group consisting of acyl and alkoxyalkyl; R.sub.10 is selected from the group consisting of hydrogen and --C(:NH)NH.sub.2 ; Z.sub.1 is selected from the group consisting of a saturated carbon carbon bond --CH.sub.2 CH.sub.2 -- and a cis unsaturated carbon carbon double bond --CH=CH--; Z.sub.2 is selected from the group consisting of a single bond or a double bond; Z.sub.3 is a single bond except when R.sub.4 is hydrogen and R.sub.5 is hydrogen and R.sub.4 and R.sub.5 are hydrogen Z.sub.3 is a double bond; Z.sub.4 is selected from the group consisting of a saturated carbon carbon bond --CH.sub.2 CH.sub.2 -- and a trans unsaturated carbon carbon bond --CH=CH--; Z.sub.5 is selected from the group consisting of a saturated carbon carbon bond --CH.sub.2 CH.sub.2 and a cis unsaturated carbon carbon double bond --CH=CH--; and wherein n is 2 to 5, m is 1 to 3 and x is 1 to 2. The wavy line in the formula indicates the stereochemistry of the attached group on the cyclopentyl ring or on the side chain and it indicates either an .alpha. or .beta. configuration. The dotted line indicates that the attached group are .alpha. oriented or on the same side of the cyclopentyl ring as the carboxyl side chain and a wedged line indicates that the .beta.-substituents are oriented on the same side of the ring as the alkyl side chain. The wavy line on the alkyl side chain indicates that the attached group may have a configuration represented by the terms sinister (S) and rectus (R) which for these compounds are equivalent nomenclature of .alpha. and .beta. respectively.
The novel and the unobvious putrescine prostaglandins and agmatine prostaglandins of the invention as embraced by Formulae 1 are primarily related to the prostaglandins, a family of naturally occurring endogenous biologically important compounds possessing diverse and valuable pharmacological properties. The prostaglandins, a family of lipid acids are generally characterized as being 20 carbon atom prostanoic derivatives and they are usually separated into categories such as prostaglandin E, F, A and B. The separation of the prostaglandins depends on the arrangements of double bonds, hydroxyl and ketone groups, for example the E-type prostaglandins have an 11.alpha.-hydroxyl group and a 9-keto group in the five-membered cyclopentyl ring while in the F-type prostaglandins the 9-position is substituted with an .alpha.-hydroxyl group and the compound still retains the 11-hydroxyl group. The A-type and B-type prostaglandins do not have the familiar 11-hydroxyl group that is present in the E's and F's. The prostaglandins are also classified as primary, secondary and tertiary depending on the number of double bonds present in the prostaglandin. For example, the primary prostaglandins containing a 13:14 double bond are called E.sub.1 and F.sub.1. The prostaglandins that contain an additional double bond at the 5:6 position are designated as E.sub.2 and F.sub.2 and the prostaglandins with an added third double bond positioned at 17:18 are termed E.sub.3 and F.sub.3 respectively with the classification also used for the various categories.
The valuable physiological properties known by the art to be possessed by the prostaglandin family includes the prostaglandin ability to stimulate or control alimentary and reproductive smooth muscles, the ability to block gastric acid and enzyme secretions by the stomach, the property to stimulate the synthesis of adrenal corticoids, and to aid in regulating blood pressure, their possible role as a mediator of hormonal functions, and their ability to inhibit platelet aggregation. While the family as a group possesses these actions, the actions of each of the E, F, A and B prostaglandins are often dissimilar and sometimes they are opposed. For example, the prostaglandins of the E-type configuration are vasodepressors and they decrease the motility of the uterus at ovulation while the prostaglandins of the F-type usually have the opposite effects. The E-prostaglandins also inhibit platelet aggregation while the F-prostaglandins are devoid of this property. The prostaglandins of the A-type structure are like the E-type with respect to their vascular smooth muscle action but they possess a differing degree of relative potency as gastrointestinal secretion regulating agents.
Even though the prostaglandins are known to possess the above mentioned valuable pharmacological utilities in vitro that could be selectively used by various glands, tissues and organs, the potential pharmaceutical utilization of these compounds has not been presently realized in vivo because the prostaglandins lack the necessary biological stability that lends itself to therapeutic application of the prostaglandins. For example, the prostaglandins of the art known biologically active E-type chemical structure in the presence of acidic conditions readily change to prostaglandins of the A-type structure that possess different biological activities, and the A-type prostaglandins under prolonged exposure to biological gastric acidic conditions isomerize to B-type prostaglandins. The prostaglandins that are known by the art to evidence widely different biological activities which make their physiological application seemingly more difficult and sometimes unpredictable in the face of these possible in vivo changes in chemical structure and physiological activities. These changes also lessen the availability of useful prostaglandin for in vivo use by changing useful prostaglandins that can be absorbed from the vascular system to inactive metabolic forms of the prostaglandins.
In the light of the above presentation, it will be easily appreciated by those versed in the art that a need exists for increasing the biological stability of the family of prostaglandins while essentially maintaining and readily making available to biological receptors the physiologically useful prostaglandins. It will also be appreciated that a need exists for providing new prostaglandin compounds that can serve as a reservoir of the prostaglandin per se for vascular circulation and subsequent availability by release of the prostaglandin from the prostaglandin compound to cells, glands and tissues for their immediate physiological use while simultaneously increasing the biological stability of the prostaglandin.
Accordingly, it is an immediate object of the present invention to make available to the art novel and unobvious prostaglandin compounds that overcome the problems often associated with the prior art.
Yet another object of the present invention is to provide new prostaglandin compounds that possess enhanced biological stability against rapid metabolism to ensure their in vivo employment for their known pharmacological properties.
Still yet another purpose of the subject invention is to provide prostaglandin compounds that can act as both an intracellular and extracellular biological reservoir of the prostaglandin for circulating within the vascular system to ensure increased availability as needed by the cells, glands and tissues for their immediate use.
Yet still another object of the invention is to provide prostaglandin compounds that possess enhanced cell membrane permeability in certain hosts for intracellular prostaglandin performance.
Another object of the invention is to provide new 4-(aminobutyl)-guanidine prostaglandins and 1,4-diaminobutane prostaglandins that possess useful properties for both in vivo and in vitro applications.
These and other features, objects and advantages of the present invention will become more readily apparent from the following detailed description of the invention taken in conjunction with the accompanying claims.